1. Field of the Invention
This invention relates to a class of .beta.-lactam antibiotics and intermediates therefor. More particularly, it relates to penicillins in which the C.3 position bears a pyrimidin-4,6-dione-2-yl group in place of the carboxy group, and to intermediates for such compounds.
2. Description of the Prior Art
The penicillins, a .beta.-lactam class of antibiotics, consist of N-acyl derivatives of 6-amino-2,2-dimethylpenam-3-carboxylic acid. Since the physicochemical and biological properties of the penicillins are largely determined by the nature of the C.6 substituent, chemical modification of the substituents on the penam nucleus has, until recently, focused on the C.6 position.
Efforts to improve the therapeutic value of the penicillins have also led to chemical modification at the C.3 position. The 3-carboxy group has been converted to a number of other groups such as salts, anhydrides, carbamyl, esters, thioacid, hydroxymethyl, acid azide, isocyanate, carbamates, hydroxamic and nitrile [Khokhlov, et al., Doklady Akad. Sci. Nauk. S.S.S.R. 135, 875-8 (1960); C.A. 55, 1139F (1961)]. A summary of such modifications is presented by Hamilton-Miller, Chemotherapia, 12, 73-88 (1967).
In addition, the 3-carboxy group has been replaced by formyl [Gottstein et al., J. Org. Chem. 31, 1922 (1966)], acid chloride [Wolfe et al, Can. J. Chem., 46, 2549 (1968)], hydroxy [Heusler, Helv. Chim. Acta, 55, 388 (1972); Sheehan and Brandt, J. Amer. Chem. Soc., 87, 5468 (1965)], diazoketone [Kleiner, Khim. Geterotsikl. Soed. 1966, 702; Ramsey and Stoodley, J. Chem. Soc. (C) 1969, 1319], carboxymethyl [Kleiner loc. cit.], chloroketones (3-COCH.sub.2 Cl) [Ramsey and Stoodley, Chem. Commun. 1970, 1517], and the N-sulfonylamides (3-CONHSO.sub.2 Me) [U.S. Pat. No. 3,641,000]. With trivial exceptions of salts certain easily hydrolyzed esters, and thioacids, all of these changes result in greatly diminished antibacterial activity.
It was recently reported, Belgian Pat. No. 821,163, granted Apr. 17, 1975, that penams in which the 3-carboxy group is replaced by a 5-tetrazolyl group are highly effective antibacterial agents. Further, Belgian Pat. No. 821,952, granted Mar. 3, 1975, describes a series of 6-[2-(pyrimidin-2,4-dione-1-yl)acetamido]-2,2-dimethylpenam-3-carboxylic acids as antibacterial agents useful against penicillinase resistant antibiotics.